Method of detecting test substance, sample analysis cartridge, and sample analyzer

ABSTRACT

In a method of detecting a test substance, a test substance is detected using a sample analysis cartridge supplied with a sample. The sample analysis cartridge includes: a passage part having a gas-phase space; and liquid containers communicating with the passage part through openings. The liquid containers include: a first liquid container containing a first liquid containing magnetic particles; and a second liquid container containing a second liquid containing a labeled substance. The magnetic particles are sequentially transported to the liquid containers through the gas-phase space in the passage part. Thus, the magnetic particles carry a complex of the test substance and the labeled substance. The test substance is detected based on the labeled substance in the complex.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to prior Japanese Patent ApplicationNo. 2015-093387 filed on Apr. 30, 2015 entitled “METHOD OF DETECTINGTEST SUBSTANCE, SAMPLE ANALYSIS CARTRIDGE, AND SAMPLE ANALYZER” theentire contents of which are hereby incorporated by reference.

BACKGROUND

There is a technology to perform sample analysis by a sample analyzerusing a cartridge-type fluid device (see, for example, U.S. Pat. No.7,708,881: Patent Document 1).

Patent Document 1 discloses a technology to analyze a sample using afluid device including liquid containers containing a liquid andmicrochannels connecting the liquid containers. A test substance iscarried by magnetic particles, which are carriers, and transported bymagnetic force. The magnetic particles carrying the test substance aretransported between the liquid containers adjacent to each other throughthe microchannel by the magnetic force. The liquid contained in theliquid containers is supplied to each liquid container through themicrochannels.

SUMMARY

A method of detecting a test substance according to a first embodimentis a method of detecting a test substance contained in a sample by useof a sample analysis cartridge supplied with the sample, the sampleanalysis cartridge including a passage part with a gas-phase space andliquid containers disposed along the passage part and communicating withthe passage part through openings, the liquid containers including afirst liquid container containing a first liquid containing magneticparticles for carrying the test substance, and a second liquid containercontaining a second liquid containing a labeled substance that can becoupled to the test substance, the method comprising: sequentiallytransporting the magnetic particles to the liquid containers through thegas-phase space in the passage part, and thus allowing the magneticparticles to carry a complex of the test substance and the labeledsubstance and detecting the test substance based on the labeledsubstance in the complex.

A sample analysis cartridge according to a second embodiment is a sampleanalysis cartridge set in a sample analyzer and supplied with a samplefor detecting a test substance contained in the sample, comprising: apassage part with a gas-phase space; and liquid containers disposedalong the passage part and communicating with the passage part throughopenings, wherein the liquid containers include a first liquid containercontaining a first liquid containing magnetic particles that carries thetest substance, and a second liquid container containing a second liquidcontaining a labeled substance that can be coupled to the testsubstance, and the liquid containers are arranged such that the magneticparticles are sequentially transported to the liquid containers throughthe gas-phase space in the passage part, and thus a complex of the testsubstance and the labeled substance is carried by the magneticparticles.

A sample analyzer according to a third aspect of the embodiment is asample analyzer which analyzes a test substance contained in a samplesupplied to a sample analysis cartridge, comprising: a setting part thatsets a sample analysis cartridge including a passage part with agas-phase space, and liquid containers disposed along the passage partand communicating with the passage part through openings, the liquidcontainers including a first liquid container containing a first liquidcontaining magnetic particles that carries the test substance, and asecond liquid container containing a second liquid containing a labeledsubstance that can be coupled to the test substance; a magnetic sourcethat generates magnetic force acting on the magnetic particles in thesample analysis cartridge set in the setting part, thereby transportingthe magnetic particles between the liquid containers; and a detectorthat detects the test substance based on the labeled substance in acomplex of the test substance and the labeled substance carried by themagnetic particles, wherein the magnetic source moves near the sampleanalysis cartridge set in the setting part, thereby sequentiallytransporting the magnetic particles to the liquid containers through thegas-phase space in the passage part.

In sample measurement using the sample analysis cartridge, it ispossible to suppress the mixing of a liquid in a liquid container into aliquid in a liquid container adjacent thereto by movement of magneticparticles.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram for explaining an overview of a method of detectinga test substance.

FIG. 2 is a diagram illustrating another configuration example of liquidcontainers and a passage part.

FIG. 3 is a schematic view for explaining an overview of a sampleanalyzer.

FIG. 4 is a plan view illustrating a configuration example of a sampleanalysis cartridge.

FIG. 5 is a schematic view illustrating a configuration example of thesample analyzer.

FIG. 6 is a diagram for explaining an example of assay.

FIG. 7 is a flowchart for explaining a flow of sample analysis.

FIG. 8 is a cross-sectional view illustrating a configuration example ofthe liquid container in the sample analysis cartridge.

FIG. 9 is a perspective view illustrating a configuration example of theliquid container.

FIG. 10A is a plan view and FIG. 10B is a cross-sectional viewillustrating a configuration example of a liquid reaction part.

FIG. 11 is a diagram illustrating another configuration example of theliquid reaction part.

FIG. 12A is a plan view and FIG. 12B is a cross-sectional viewillustrating a configuration example of a third liquid container.

FIG. 13 is a cross-sectional view for explaining transportation ofmagnetic particles.

FIG. 14 is a cross-sectional view for explaining transportation of themagnetic particles between the liquid containers.

FIG. 15A is a cross-sectional view during magnetic collection, FIG. 15Bis a cross-sectional view during dispersion, and FIG. 15C is across-sectional view during agitation for explaining an agitationoperation in the liquid reaction part.

FIG. 16A is a diagram illustrating an agitation operation example andFIG. 16B is a diagram illustrating another agitation operation examplein a second liquid container.

FIG. 17 is a cross-sectional view illustrating a configuration exampleof an air chamber and a valve part.

FIG. 18 is a schematic plan view illustrating a configuration example ofa sample flow path.

FIG. 19 is a schematic plan view illustrating a configuration example ofa mixed liquid flow path.

FIG. 20 is a schematic cross-sectional view along the mixed liquid flowpath illustrated in FIG. 19.

FIG. 21 is a first diagram illustrating another configuration exampleregarding the mixed liquid flow path.

FIG. 22 is a second diagram illustrating another configuration exampleregarding the mixed liquid flow path.

FIG. 23 is a third diagram illustrating another configuration exampleregarding the mixed liquid flow path.

FIG. 24 is a fourth diagram illustrating another configuration exampleregarding the mixed liquid flow path.

FIG. 25 is a fifth diagram illustrating another configuration exampleregarding the mixed liquid flow path.

FIG. 26 is a schematic plan view illustrating a configuration example ofan R5 flow path.

FIG. 27 is a schematic perspective cross-sectional view illustrating aconfiguration example of a detection tank.

FIG. 28 is a schematic plan view illustrating a configuration example ofthe detection tank.

FIG. 29 is a schematic perspective view illustrating a configurationexample of the respective parts in the sample analyzer.

FIG. 30 is a schematic side view illustrating a configuration example ofa plunger.

FIG. 31 is a schematic perspective view illustrating a configurationexample of a heat block.

EMBODIMENTS

With reference to the drawings, embodiments are described below.

(Overview of Method of Detecting Test Substance)

With reference to FIG. 1, description is given of an overview of amethod of detecting a test substance according to this embodiment.

The method of detecting a test substance according to this embodiment isa method of detecting a test substance contained in a sample by use of asample analysis cartridge supplied with the sample. Sample analysiscartridge 100 is capable of receiving a sample, and is inserted intosample analyzer 500 to enable sample analyzer 500 to analyze the sample.A sample such as tissues obtained from a patient or a body fluid and ablood obtained from the patient is injected into sample analysiscartridge 100. The cartridge having the sample injected therein is setin setting part 70 in sample analyzer 500. The sample injected intosample analysis cartridge 100 is analyzed by a predetermined assay basedon functions of the cartridge and functions of the analyzer.

Sample analysis cartridge 100 includes passage part 20 having agas-phase space, liquid containers 10 disposed along passage part 20 andcommunicating with passage part 20 through openings 12, and detectiontank 30 for detecting test substance 41.

Liquid containers 10 include: first liquid container 10 a containingfirst liquid 11 a containing magnetic particles 40 for carrying testsubstance 41; and second liquid container 10 b containing second liquid11 b containing labeled substance 42 that can be coupled to testsubstance 41. Liquid containers 10 may further include a liquidcontainer containing another liquid.

The level of the liquid contained in each of liquid containers 10 is notparticularly limited as long as the container contains an amount ofliquid required for detection and there is the gas-phase space inpassage part 20. For example, FIG. 1 illustrates an example where thelevels of the liquids contained in liquid containers 10 are higher thanthe openings of the liquid containers. Therefore, in FIG. 1, the liquidscontained in liquid containers 10 are also in passage part 20 aboveopenings 12. Here, the gas-phase space means a space filled with gas,through which magnetic particles 40 invariably pass when magneticparticles 40 are transported from the liquid in one of liquid containers10 to the liquid in liquid container 10 adjacent thereto. Note that theinside of passage part 20 may be entirely set as the gas-phase space ormay be partially set as the gas-phase space. To be more specific, a partof a transportation path of magnetic particles 40 in passage part 20between two adjacent liquid containers 10 may be set as the gas-phasespace. Note that, as for the gas, air is preferably used, but nitrogenor the like can also be used. Moreover, FIG. 1 illustrates an examplewhere the opening area of each of openings 12 is smaller than the areaof the bottom inner surface of each of liquid containers 10.

Liquid containers 10 may be configured in an empty state of containingno liquids therein, respectively, as an initial state, and alsoconfigured to be supplied with the liquids, respectively, upon usage ofsample analysis cartridge 100. More specifically, there is a separateliquid chamber storing a liquid aside from liquid containers 10, and theliquids may be supplied to liquid containers 10 from the liquid chamberupon usage. Alternatively, sample analyzer 500 may be configured, forexample, to store liquids and inject the liquids into liquid containers10 upon usage.

The gas-phase space is provided in passage part 20. A gas-liquidinterface is formed between the liquids in liquid containers 10 and thegas-phase space.

In sample analysis cartridge 100, test substance 41 is carried bymagnetic particles 40 and transported to respective liquid containers 10together with magnetic particles 40. Magnetic particles 40 aretransported passing through the gas-phase space in passage part 20.Magnetic particles 40 are transported by magnetic force between adjacentliquid containers 10. The transportation of magnetic particles 40 by themagnetic force is performed using magnetic source 50 in sample analyzer500.

With such a configuration, in the method of detecting a test substanceaccording to this embodiment, magnetic particles 40 for carrying testsubstance 41 are sequentially transported to the liquid containers 10,thereby allowing magnetic particles 40 to carry a complex of testsubstance 41 and labeled substance 42. Magnetic particles 40 aretransported through the gas-phase space in passage part 20 betweenadjacent liquid containers 10. During the transportation process ofmagnetic particles 40, test substance 41 is carried by magneticparticles 40 in first liquid container 10 a, and labeled substance 42 iscoupled to test substance 41 in second liquid container 10 b. Next, inthis embodiment, test substance 41 is detected based on labeledsubstance 42 in the complex. Magnetic particles 40 carrying the complexare transported to detection tank 30. In detection tank 30, labeledsubstance 42 and a substrate react with each other. In detection tank30, test substance 41 is detected by detector 60 in sample analyzer 500based on labeled substance 42.

Magnetic source 50 is, for example, a permanent magnet or anelectromagnet. Magnetic source 50 generates magnetic force acting onmagnetic particles 40 in sample analysis cartridge 100 set in settingpart 70, thereby transporting magnetic particles 40 between liquidcontainers 10. For example, magnetic source 50 itself moves to transportmagnetic particles 40. More than one magnetic source 50 may be disposedalong the transportation path of magnetic particles 40, and magneticsources 50 generating the magnetic force may be switched to transportmagnetic particles 40. In the example of FIG. 1, magnetic source 50moves near sample analysis cartridge 100 set in setting part 70, therebysequentially transporting magnetic particles 40 to liquid containers 10through the gas-phase space in passage part 20.

During the transportation of magnetic particles 40, magnetic particles40 move into the gas-phase space in passage part 20 by breaking throughthe gas-liquid interface from inside the liquid in the liquid container10, and then move into the liquid in adjacent liquid container 10 bybreaking through the gas-liquid interface from the gas-phase space.Thus, the mixing of the liquids in respective liquid containers 10 issuppressed during the transportation of magnetic particles 40 betweenadjacent liquid containers 10. During the transportation of magneticparticles 40, the liquids in respective liquid containers 10 may leakinto passage part 20 from openings 12 as long as the amount of theliquid leaking into passage part 20 is not as large as that is mixedwith the liquid in another liquid container 10 and the gas-phase spaceremains in passage part 20. Even in such a case, magnetic particles 40can move through the gas-phase space in passage part 20. Thus, it ispossible to suppress the mixing of the liquid in liquid container 10into the liquid in liquid container 10 adjacent thereto by the movementof magnetic particles 40.

As described above, in the method of detecting a test substanceaccording to this embodiment, it is possible to suppress the mixing ofthe liquid in liquid container 10 into the liquid in liquid container 10adjacent thereto by the movement of magnetic particles 40 in sampleanalysis using sample analysis cartridge 100.

FIG. 2 is a diagram illustrating another configuration example of liquidcontainers 10 and passage part 20.

In the configuration example of FIG. 2, the levels of the liquidscontained in liquid containers 10 are set lower than openings 12. Inthis case, magnetic particles 40 are pulled up to the gas-phase space inpassage part 20 from inside the liquid 11 a in first liquid container 10a, and then transported to second liquid container 10 b. FIG. 2 alsoillustrates an example where the opening area of the openings 12 is setlarger than that of openings 12 illustrated in FIG. 1.

In the configuration examples of FIGS. 1 and 2, passage part 20 isdisposed above respective liquid containers 10. To be more specific,passage part 20 is disposed close to the upper surface of sampleanalysis cartridge 100, and openings 12 are formed in upper parts ofliquid containers 10. Therefore, the gas-phase space in passage part 20,through which magnetic particles 40 are transported, can be easilyprovided. In this case, magnetic source 50 in sample analyzer 500outside sample analysis cartridge 100 can be set close to passage part20. As a result, stronger magnetic force can be generated to act onmagnetic particles 40. Thus, magnetic particles 40 can be efficientlytransported. Moreover, just by disposing magnetic source 50 close topassage part 20, magnetic particles 40 can be easily allowed to passthrough openings 12.

Moreover, in the configuration examples of FIGS. 1 and 2, magneticparticles 40 are transported by moving magnetic source 50 along passagepart 20 above sample analysis cartridge 100. In this case, magneticparticles 40 can be transported while allowing stronger magnetic forceto act on magnetic particles 40 by disposing magnetic source 50 close topassage part 20. As a result, magnetic particles 40 can be easilytransported so as to pass through the gas-phase space in passage part20.

(Overview of Sample Analyzer)

FIG. 3 illustrates an overview of sample analyzer 500 according to thisembodiment. Sample analyzer 500 can determine whether or not there is atest substance in a sample and can also determine the concentration ofthe test substance in the sample. Sample analyzer 500 is small and has asize that can be installed on a desk in an examination room where adoctor examines a patient, for example. In this embodiment, the size ofsample analyzer 500 is, for example, about 150 cm² to 300 cm² ininstallation area. Sample analyzer 500 has a slot into which sampleanalysis cartridge 100 is inserted, for example. Sample analysiscartridge 100 inserted into the slot is set in setting part 550 in thesample analyzer. Sample analyzer 500 performs analysis processing onsample analysis cartridge 100 set in setting part 550.

(Configuration Example of Sample Analysis Cartridge)

FIG. 4 illustrates a specific configuration example of sample analysiscartridge 100 according to this embodiment. Sample analysis cartridge100 may be a disposable cartridge. In such a case, sample analysiscartridge 100 is stored in a state of being housed in a package, and istaken out of the package for use.

Sample analysis cartridge 100 includes liquid containers 110 containingliquids such as a sample, a reagent and a cleaning liquid. Some reagentscontain magnetic particles, which react with a substance containing atest substance. Sample analysis cartridge 100 includes detection tank170 and liquid reaction part 112.

In this embodiment, liquid containers 110 include first liquid container111, third liquid container 113, second liquid container 114, and fourthliquid container 115. First liquid container 111, third liquid container113, second liquid container 114, and fourth liquid container 115 aswell as liquid reaction part 112 are arranged along passage part 116with a gas-phase space. The magnetic particles are transported betweenrespective liquid containers 110 through the gas-phase space in passagepart 116.

The sample is injected into blood cell separator 120 in sample analysiscartridge 100. Sample analysis cartridge 100 having blood cell separator120 sealed therein is inserted into sample analyzer 500.

Sample analysis cartridge 100 has air chamber 130. Air sent from airchamber 130 transports some of the liquids in sample analysis cartridge100.

(Configuration Example of Sample Analyzer)

FIG. 5 illustrates a configuration example of sample analyzer 500.Sample analyzer 500 includes heat blocks 510, permanent magnet 520,plunger 530, detector 540, and setting part 550. Setting part 550 holdssample analysis cartridge 100. Setting part 550 may have any structurethat can hold sample analysis cartridge 100.

Heat blocks 510 adjust the temperature of sample analysis cartridge 100inserted into sample analyzer 500. Heat blocks 510 may be disposed so asto come into contact with the upper and lower surfaces of sampleanalysis cartridge 100. Heat blocks 510 may include a part of or all ofsetting part 550.

In sample analyzer 500, magnetic particles contained in some of theliquid containers in sample analysis cartridge 100 are transported bymagnetic force of permanent magnet 520. As for magnetic source 50 insample analyzer 500, an electromagnet other than permanent magnet 520may be used.

In sample analyzer 500, plunger 530 pushes down air chamber 130 insample analysis cartridge 100. Air chamber 130 is pushed down by plunger530 to send air, thereby transporting some of the liquids in sampleanalysis cartridge 100. Sample analyzer 500 can control the amount ofair sent from air chamber 130 by adjusting how much the air chamber ispushed down by plunger 530. Sample analyzer 500 can adjust the amount ofthe liquids to be transported, by controlling the air amount. Sampleanalyzer 500 can apply a negative pressure to sample analysis cartridge100 by returning plunger 530 that is pushed down. Sample analyzer 500can transport the transported liquid in an opposite direction by thenegative pressure. Some of the liquids in sample analysis cartridge 100are moved back and forth in a flow path inside sample analysis cartridge100 by the vertical movement of plunger 530.

Heat block 510 has holes 511 for permanent magnet 520 and plunger 530 toaccess sample analysis cartridge 100. Holes 511 are provided in heatblock 510 disposed on the upper surface of sample analysis cartridge100, for example. When permanent magnet 520 and plunger 530 accesssample analysis cartridge 100 from both directions, holes may beprovided in both of heat blocks 510 on the upper and lower surfaces ofsample analysis cartridge 100. Some of holes 511 provided in heat block510 may be recesses or grooves that do not penetrate heat block 510.

Detector 540 may be a light detector configured to detect lightgenerated by reaction between a reagent and a complex containing a testsubstance. Detector 540 is, for example, a photomultiplier tube.

(Explanation of Assay)

With reference to FIG. 6, an overview of assay (analysis method) isdescribed.

Test substance 190 includes, for example, an antigen. As an example, inFIG. 6, the antigen is a hepatitis B surface antigen. The test substancemay be an antigen, an antibody, or one or more of other proteins.

An R1 reagent contains capture substance 192 to be coupled to testsubstance 190. Capture substance 192 includes, for example, an antibodyto be coupled to test substance 190. In the example of FIG. 6, theantibody is a biotin-coupled HBs monoclonal antibody.

Test substance 190 coupled to the R1 reagent is coupled to magneticparticle 191. Magnetic particle 191 is contained in an R2 reagent.Magnetic particle 191 serves as a carrier of the test substance. In theexample of FIG. 6, magnetic particle 191 is, for example, astreptavidin-coupled magnetic particle having its surface coated withavidin. The avidin of magnetic particle 191 is likely to be coupled tothe biotin of the R1 reagent. Thus, connectivity between magneticparticle 191 and capture substance 192 in the R1 reagent is improved.

The coupled body of test substance 190, capture substance 192, andmagnetic particle 191 is separated from an unreacted substance bycleaning with a cleaning liquid. After the cleaning, the coupled body oftest substance 190, capture substance 192, and magnetic particle 191reacts with labeled substance 193 contained in an R3 reagent.

Labeled substance 193 includes, for example, a labeled antibody. In theexample of FIG. 6, the labeled antibody is an ALP labeled HBsAgmonoclonal antibody. Note that, in the case of the example of FIG. 6,labeled substance 193 is coupled to test substance 190 in the coupledbody of test substance 190, capture substance 192, and magnetic particle191. Labeled substance 193 may be coupled to capture substance 192 ormay be coupled to magnetic particle 191. The labeled substance may be anantigen, an antibody, or one or more of other proteins, and is selectedaccording to test substance 190.

Hereinafter, a reactant obtained by reacting at least test substance 190and magnetic particle 191 with labeled substance 193 is called “complex190 c”. Complex 190 c may contain capture substance 192 in the R1reagent.

Complex 190 c is separated from the unreacted substance by cleaning withthe cleaning liquid. After the cleaning, complex 190 c is combined withan R4 reagent. A reactant obtained by reacting complex 190 c with the R4reagent is called a “mixed liquid”. The R4 reagent has a compositionthat facilitates light emission by complex 190 c. The R4 reagent is, forexample, a buffer liquid.

An R5 reagent is added to the mixed liquid. The R5 reagent includes, forexample, a substrate that reacts with complex 190 c to facilitate lightemission. Complex 190 c reacts with the substrate in the R5 reagent.Detector 540 measures emission intensity of light generated by reactionbetween complex 190 c and the R5 reagent.

FIG. 6 illustrates an example of combination where test substance 190and labeled substance 193 are the antigen and antibody. However, anycombination other than the combination of antigen and antibody may alsobe employed. For example, the following combinations may be used, suchas (1) test substance 190 is the antibody and labeled substance 193 isthe antigen, (2) test substance 190 is the antibody and labeledsubstance 193 is the antibody, (3) test substance 190 is the antigen andlabeled substance 193 is the antigen, and (4) test substance 190 is theantigen and antibody, and labeled substance 193 is the antigen andantibody.

(Description of Operations According to Embodiment)

FIG. 7 illustrates an operation example when the above assay isperformed using sample analyzer 500 and sample analysis cartridge 100according to this embodiment. In the description of the operations, FIG.4 is referred to for the configuration of sample analysis cartridge 100,and FIG. 5 is referred to for sample analyzer 500.

In Step S1, sample analysis cartridge 100 is opened from a package.

In Step S2, a sample obtained from a patient is injected into blood cellseparator 120 in the opened sample analysis cartridge 100. After theinjection of the sample, sample analysis cartridge 100 is inserted intosample analyzer 500 and then set in setting part 550. The sampleinjected into sample analysis cartridge 100 flows through sample flowpath 140 in sample analysis cartridge 100.

In Step S3, heat blocks 510 adjusts the temperature of the insertedsample analysis cartridge 100. For example, heat blocks 510 heat upsample analysis cartridge 100.

In Step S4, sample analyzer 500 reacts the antibody contained in the R1reagent with the antigen that is test substance 190. Sample analyzer 500uses plunger 530 to push down air chamber 130 a. The R1 reagent ispushed out to sample flow path 140, through which test substance 190flows, by the air sent from air chamber 130 a.

Sample analyzer 500 moves up and down plunger 530. The mixed liquid ofthe sample and the R1 reagent is moved back and forth within the sampleflow path 140 by a negative pressure and a positive pressure, which arealternately generated according to the up-and-down movement of plunger530. The mixed liquid is agitated by being moved back and forth withinsample flow path 140. Thus, the reaction between the sample and the R1reagent is facilitated. As a result of the reaction, an antigen-antibodyreactant is generated in the mixed liquid of the sample and the R1reagent. Sample analyzer 500 further pushes down plunger 530 to push outthe mixed liquid of the sample and the R1 reagent to liquid reactionpart 112.

In Step S5, sample analyzer 500 reacts magnetic particle 191 containedin the R2 reagent with the antigen-antibody reactant contained in themixed liquid of the sample and the R1 reagent. Sample analyzer 500 usesthe magnetic force of permanent magnet 520 to transport magneticparticle 191 from first liquid container 111 to liquid reaction part112. In liquid reaction part 112, a coupled body of magnetic particle191 is generated by the reaction between magnetic particle 191 and theantigen-antibody reactant.

In Step S6, sample analyzer 500 uses the magnetic force of permanentmagnet 520 to transport the coupled body of magnetic particle 191 tothird liquid container 113. Sample analyzer 500 separates the coupledbody of magnetic particle 191 from an unreacted substance in thirdliquid container 113. The unreacted substance is removed by cleaning.

In Step S7, sample analyzer 500 uses the magnetic force of permanentmagnet 520 to transport the cleaned coupled body of magnetic particle191 to second liquid container 114. Sample analyzer 500 reacts thelabeled antibody contained in the R3 reagent with the coupled body ofmagnetic particle 191 in second liquid container 114. Complex 190 c isgenerated by the reaction between the labeled antibody and the coupledbody of magnetic particle 191.

In Step S8, sample analyzer 500 uses the magnetic force of permanentmagnet 520 to transport complex 190 c to third liquid container 113. Anunreacted substance is removed by cleaning.

In Step S9, sample analyzer 500 uses the magnetic force of permanentmagnet 520 to transport complex 190 c to fourth liquid container 115.Complex 190 c reacts with the buffer liquid contained in the R4 reagent.In fourth liquid container 115, complex 190 c reacts with the bufferliquid contained in the R4 reagent. Sample analyzer 500 uses plunger 530to push down air chamber 130 b, and pushes out the mixed liquid ofcomplex 190 c and the buffer liquid to detection tank 170 through mixedliquid flow path 150.

In Step S10, the light emitting substrate contained in the R5 reagent isadded to the mixed liquid of complex 190 c and the buffer liquid. Sampleanalyzer 500 uses plunger 530 to push down air chamber 130 c, and pushesout the R5 reagent to detection tank 170 through R5 flow path 160. Indetection tank 170, the R5 reagent is added to the mixed liquid ofcomplex 190 c and the buffer liquid. The light emitting substrate reactswith complex 190 c.

In Step S11, detector 540 detects light generated by the reactionbetween the labeled antibody in complex 190 c and the light emittingsubstrate. Detector 540 measures emission intensity of the light, forexample.

In Step S12, sample analysis cartridge 100 is taken out of sampleanalyzer 500 and discarded upon completion of the measurement. No sampleor reagent leaks to the outside from the discarded sample analysiscartridge 100. Thus, biohazard risks can be reduced. Moreover, sampleanalyzer 500 also generates no waste liquid.

[Configuration of Respective Parts in Sample Analysis Cartridge]

(Configuration of Liquid Container)

FIG. 8 illustrates a configuration example of liquid containers 110 insample analysis cartridge 100. Liquid containers 110 may be recess partsformed integrally with cartridge main body 100 a, for example.

Sample analyzer 500 executes the assay by transporting magneticparticles 191 through the gas-phase space in passage part 116 betweenliquid containers 110. Thus, sample analyzer 500 can execute the assayfor analysis while suppressing the mixing of the liquid in liquidcontainer 110 into the liquid in liquid container 110 adjacent theretoby the movement of magnetic particles 191. When the liquid contained inliquid container 110 is mixed into the liquid contained in anotherliquid container 110 by the movement of magnetic particles 191, reactionconditions change in the liquid in another liquid container 110. Such achange in reaction conditions reduces a reaction effect of the sampleand the substance in the reagent. As a result, there may be influence onaccuracy and the like of the measurement result obtained by sampleanalyzer 500. Therefore, the analysis accuracy of sample analyzer 500 isimproved by suppressing the mixing of the liquid contained in liquidcontainer 110 into the liquid contained in another liquid container 110.

Moreover, it is no longer required to consider the compatibility betweenthe liquids contained in liquid containers 110 by suppressing the mixingof the liquid contained in liquid container 110 into the liquidcontained in another liquid container 110. Thus, the degree of freedomof selection of the liquids contained in liquid containers 110 isincreased. As a result, combinations of reagents corresponding tovarious test items can be contained in liquid containers 110. Sincevarious combinations of reagents can be contained in liquid containers110, the type of the cartridge can be diversified.

Meanwhile, each of liquid containers 110 has a liquid storage portioncommunicating with a surface region connected to passage part 116through opening 211 a. More specifically, liquid container 110 hasopening 211 a and recessed liquid storage part 211 communicating withopening 211 a and capable of storing a liquid inside. In thisembodiment, each of first liquid container 111, third liquid container113, and second liquid container 114 (see FIG. 4) has opening 211 a andliquid storage part 211. Opening 211 a is formed in the upper part ofliquid container 110. Around opening 211 a, step part 212 (see FIG. 9)is provided. The liquid contained in liquid container 110 may be notonly in liquid storage part 211 but also in passage part 116 aboveliquid container 110. Moreover, sample analysis cartridge 100 has aZ2-side surface covered with sheet 102

In the configuration example illustrated in FIG. 8, the area of bottominner surface 211 b of liquid storage part 211 is larger than theopening area of opening 211 a. Therefore, the amount of the liquid thatcan be contained in liquid storage part 211 can be increased.

Liquid containers 110 in sample analysis cartridge 100 may have astructure to further suppress the mixing of the liquid contained inliquid container 110 into the liquid contained in another liquidcontainer 110 by the movement of magnetic particles 191. For example, assuch a structure, grooves 216 may be provided by denting the surface ofpassage part 116.

The liquids in respective liquid containers 110 may leak into passagepart 116 (see FIG. 9) through openings 211 a as long as the amount ofthe liquid leaking into passage part 116 is not as large as that ismixed with the liquid in another liquid container 110 and the gas-phasespace remains in passage part 116. In this case, even if the liquidleaks out to passage part 116, magnetic particles 191 are transported toadjacent liquid container 110 through the gas-phase space in passagepart 116. Thus, it is possible to suppress the mixing of the liquidcontained in liquid container 110 into the liquid contained in anotherliquid container 110 by the movement of magnetic particles 191. When astructure is provided to further suppress the mixing of the liquidcontained in liquid container 110 into the liquid contained in anotherliquid container 110 by the movement of magnetic particles 191, it ispossible to further suppress the mixing of the liquid contained inliquid container 110 into the liquid contained in another liquidcontainer 110 by the movement of magnetic particles 191. For example,when recessed grooves 216 are provided in passage part 116, even if theliquid contained in liquid container 110 is mixed with the liquidcontained in another liquid container 110 in the groove, magneticparticles 191 are transported to adjacent liquid container 110 throughthe gas-phase space in passage part 116. Thus, it is possible to furthersuppress the mixing of the liquid contained in liquid container 110 intothe liquid contained in another liquid container 110 by the movement ofmagnetic particles 191.

Cover part 117 may be provided on the outer surface side of sampleanalysis cartridge 100. In the configuration example of FIG. 8, passagepart 116 is disposed so as to be exposed to the upper surface of sampleanalysis cartridge main body 100 a, and sample analysis cartridge 100has cover part 117 covering liquid containers 110 and passage part 116.Cover part 117 is configured to sandwich and hold the liquid between theliquid containers and cover part 117.

In the configuration example of FIG. 8, cover part 117 covers the uppersurfaces of liquid containers 110 and passage part 116 from the uppersurface side. Also, cover part 117 comes into contact with the uppersurface of the liquid in the passage part 116 above the liquidcontainers 110. More specifically, the liquid is sandwiched from aboveand below by liquid containers 110 and cover part 117. Thus, liquidcontainers 110 and passage part 116 may be disposed so as to be exposedto the upper surface of sample analysis cartridge main body 100 a andcovered with cover part 117. Accordingly, permanent magnet 520 can comeclose to liquid containers 110 and passage part 116 from outside sampleanalysis cartridge 100. Thus, stronger magnetic force can be generatedto act on magnetic particles 191 for efficient transportation ofmagnetic particles 191.

Cover part 117 includes a flat sheet member, for example. Cover part 117may be formed using a material having a hydrophobic surface on theliquid container 110 side. Thus, effective action of surface tension ofthe liquid can be achieved. The hydrophobic material may be a coatingmaterial provided on the surface of the sheet member of cover part 117.The sheet member itself included in cover part 117 may be formed using ahydrophobic material.

(Liquid Reaction Part)

FIG. 10 illustrates a configuration example of liquid reaction part 112.In sample analysis cartridge 100, the sample flowing in from blood cellseparator 120 is mixed with the R1 reagent on sample flow path 140, andthe mixed liquid is discharged to liquid reaction part 112.

Liquid reaction part 112 has inlet 213 for supplying the mixed liquid ofthe sample and the R1 reagent to the inside. Inlet 213 is connected tosample flow path 140 and is disposed in a peripheral portion of liquiddisposition part 214. FIG. 10 illustrates a configuration example whereliquid disposition part 214 extends linearly in the X direction. In thiscase, inlet 213 is disposed at the end of liquid disposition part 214.Step part 215 is provided along the peripheral edge of liquiddisposition part 214 including inlet 213. Inlet 213 is an opening formedin the surface of liquid disposition part 214, for example.

FIG. 11 illustrates another configuration example of liquid reactionpart 112.

As illustrated in FIG. 11, liquid reaction part 112 may have a shapeother than the linearly extending shape. Here, liquid reaction part 112has approximately circular liquid disposition part 214. Inlet 213 isdisposed in the surface of a peripheral portion of liquid dispositionpart 214. Step part 215 is formed in a peripheral portion of liquiddisposition part 214.

(Third Liquid Container)

As illustrated in FIG. 12A, third liquid container 113 is disposed onthe upstream side or downstream side of the liquid container in whichmagnetic particles 191 transported by the magnetic force reacts with thereagent. Third liquid containers 113 may be disposed on both of theupstream side and downstream side of the liquid container. Note that theupstream side and downstream side described here mean a transportationdirection of magnetic particles 191 and not the direction in which theliquid flows. Third liquid containers 113 may be arranged on theupstream side or downstream side of the liquid container. For example,third liquid container 113 a and third liquid container 113 b are on theupstream side of second liquid container 114, and third liquid container113 c is on the downstream side of second liquid container 114.

As illustrated in FIG. 12B, each of third liquid containers 113 a to 113c includes liquid storage part 211 having opening 211 a. Magneticparticles 191 can be dispersed into a larger amount of cleaning liquidby transporting magnetic particles 191 into liquid storage parts 211through openings 211 a. Thus, cleaning efficiency can be improved.

(Second Liquid Container and Fourth Liquid Container)

For second liquid container 114, the same configuration as that of thirdliquid container 113 can be adopted. By providing liquid storage part211 in second liquid container 114, the amount of the R3 reagent inwhich magnetic particles 191 are to be dispersed can be increased. Thus,reaction efficiency can be improved. The same applies to fourth liquidcontainer 115.

(Transportation of Magnetic Particles)

In this embodiment, sample analyzer 500 transports magnetic particles191 through the gas-phase space in passage part 116 between liquidcontainers 110. During the process of transporting magnetic particles191 between liquid containers 110, the antibody, antigen and the likecontained in the liquid adhere to magnetic particles 191, and reactionrequired for the assay progresses. Thus, it is possible to suppress themixing of the liquid contained in liquid container 110 into the liquidcontained in another liquid container 110 by the movement of magneticparticles 191.

FIG. 13 illustrates details of the transportation of magnetic particles191 between liquid containers 110.

Sample analyzer 500 moves permanent magnet 520 close to liquid container110 in sample analysis cartridge 100, thereby aggregating magneticparticles 191 in the liquid on the surface of liquid container 110.Sample analyzer 500 moves permanent magnet 520 to transport magneticparticles 191 aggregated on the gas-liquid interface. Sample analyzer500 moves permanent magnet 520 to transport the aggregated magneticparticles 191 to the passage part 116 from inside the liquid. Themagnetic force of permanent magnet 520 transports the aggregatedmagnetic particles 191 to passage part 116 from inside the liquid beyondthe gas-liquid interface. Sample analyzer 500 further moves permanentmagnet 520 to transport aggregated magnetic particles 191 to anotherliquid container 110.

Liquid containers 110 associated with the transportation of magneticparticles 191 may be arranged linearly in the longitudinal direction ofsample analysis cartridge 100. In the configuration example illustratedin FIG. 4, first liquid container 111, liquid reaction part 112, thirdliquid container 113, second liquid container 114, and fourth liquidcontainer 115 are linearly arranged. By linearly arranging liquidcontainers 110, it is possible to suppress magnetic particles 191remaining in liquid containers 110 and passage part 116.

The liquid may adhere to magnetic particles 191 transported to passagepart 116 from inside the liquid. As illustrated in FIG. 13, a structureto remove the liquid adhering to magnetic particles 191 may be providedin passage part 116 between liquid containers 110. For example, as sucha structure, grooves 216 may be provided by denting the surface ofpassage part 116. Thus, a structure is realized, in which the liquidadhering to magnetic particles 191 is likely to fall onto the bottom ofgroove 216 from passage part 116. Note that, as described above, whengrooves 216 are provided, it is possible to further suppress the mixingof the liquid leaking from liquid container 110 into the liquidcontained in another liquid container 110 by the movement of magneticparticles 191.

(Transportation of Magnetic Particles to Respective Liquid Containers)

Here, description is given of transportation of magnetic particles 191between adjacent liquid containers. In a configuration exampleillustrated in FIG. 14, magnetic particles 191 are transported by themagnetic force to liquid reaction part 112, third liquid container 113a, third liquid container 113 b, second liquid container 114, thirdliquid container 113 c, and fourth liquid container 115 in this order,starting from first liquid container 111 on the upstream side in thetransportation direction.

Liquid reaction part 112 and third liquid container 113 a are adjacentto each other through passage part 116. Magnetic particles 191 aretransported from liquid reaction part 112 to third liquid container 113a through passage part 116. Unwanted substances adhering to magneticparticles 191 are dispersed into the cleaning liquid. Thus, only acoupled body of test substance 190 and magnetic particle 191 can betaken out of liquid reaction part 112 and transported into the cleaningliquid in third liquid container 113 a. Thus, the unwanted substancesmixed into the cleaning liquid together with the magnetic particles canbe reduced. Therefore, the cleaning treatment can be efficientlyperformed. The unwanted substances are substances not required formeasurement of test substance 190, such as components other than testsubstance 190 contained in the sample and components unreacted with testsubstance 190 contained in the reagent.

Third liquid container 113 a and third liquid container 113 b areadjacent to each other through passage part 116. Magnetic particles 191are transported to third liquid container 113 b from third liquidcontainer 113 a. More specifically, magnetic particles 191 aftercleaning treatment are subjected again to cleaning treatment in anotherthird liquid container 113 b through passage part 116. Thus, thecleaning treatment can be more effectively performed.

Third liquid container 113 b and second liquid container 114 areadjacent to each other through passage part 116. Magnetic particles 191are transported to second liquid container 114 from third liquidcontainer 113 b. Thus, it is possible to suppress transporting of someof the unwanted substances dispersed into the cleaning liquid in thirdliquid container 113 b to second liquid container 114 together withmagnetic particles 191. In second liquid container 114, magneticparticles 191 carry complex 190 c of test substance 190 and labeledsubstance 193.

Note that second liquid container 114 is adjacent to third liquidcontainers 113. Magnetic particles 191 are transported to third liquidcontainer 113 b on the upstream side, second liquid container 114, andthird liquid container 113 c on the downstream side. Thus, mixing ofunwanted substances into second liquid container 114 and carryover ofunwanted substances from second liquid container 114, such as unreactedlabeled substance 193 that has formed no complex 190 c with testsubstance 190 can be efficiently suppressed.

Third liquid container 113 c and fourth liquid container 115 areadjacent to each other. Magnetic particles 191 carrying complex 190 care transported to fourth liquid container 115 through passage part 116,and thus dispersed into the buffer liquid. Accordingly, the amount ofunwanted substances adhering to magnetic particles 191 carrying complex190 c can be reduced. Thus, it is possible to suppress the transportingof the unwanted substances such as unreacted labeled substance 193 tofourth liquid container 115 together with magnetic particles 191.

(Agitation Operation)

An agitation operation using permanent magnet 520 is described. In theagitation operation, magnetic particles 191 are dispersed in the liquidby periodically changing the direction or strength of magnetic forceacting on magnetic particles 191, for example. FIG. 15 illustrates anagitation operation for reacting magnetic particles 191 with anantigen-antibody reactant in liquid reaction part 112.

In FIG. 15A, sample analyzer 500 uses permanent magnet 520 to transportmagnetic particles 191 from first liquid container 111 to liquidreaction part 112. Sample analyzer 500 moves permanent magnet 520 closeto sample analysis cartridge 100 to transport magnetic particles 191 inan aggregated state.

In FIG. 15B, sample analyzer 500 separates permanent magnet 520 fromsample analysis cartridge 100 to disperse magnetic particles 191 inliquid reaction part 112. More specifically, the strength of themagnetic force acting on magnetic particles 191 is changed. Theagitation of magnetic particles 191 is facilitated by dispersingmagnetic particles 191 in liquid reaction part 112.

In FIG. 15C, sample analyzer 500 moves permanent magnet 520 separatedfrom sample analysis cartridge 100 to agitate dispersed magneticparticles 191. Sample analyzer 500 agitates magnetic particles 191 bymoving the magnet in the width direction or length direction of sampleanalysis cartridge 100 or in a circular orbit.

By periodically repeating such operations, magnetic particles 191 aredispersed in the liquid. Thus, the reaction can be efficientlyprogressed. In this embodiment, a magnet with strong magnetic force,such as a permanent magnet, is preferably used to transport magneticparticles 191 beyond the surface tension of the liquid. Therefore, whensample analysis cartridge 100 is close to permanent magnet 520, magneticparticles 191 are aggregated, inhibiting efficient agitation. Theagitation of magnetic particles 191 can be facilitated by controllingthe distance between sample analysis cartridge 100 and permanent magnet520.

FIG. 16 illustrates another agitation example according to thisembodiment.

FIG. 16A illustrates an agitation operation example in second liquidcontainer 114. In this agitation operation example, magnetic particles191 are moved up and down in liquid container 110. Sample analyzer 500moves permanent magnet 520 in the thickness direction of sample analysiscartridge 100 in second liquid container 114. As a result, the strengthof the magnetic force acting on magnetic particles 191 is changed. Bymoving permanent magnet 520 in the thickness direction of sampleanalysis cartridge 100, a coupled body of labeled substance 193 andmagnetic particle 191 is agitated in a depth direction of second liquidcontainer 114. The agitation is facilitated entirely in the depthdirection of second liquid container 114 rather than agitating only inthe surface of second liquid container 114.

FIG. 16B illustrates another agitation operation example in secondliquid container 114. In the example of FIG. 16B, permanent magnets 520are disposed on the upper surface side and lower surface side of sampleanalysis cartridge 100, respectively. By alternately moving permanentmagnets 520 close to above and below liquid container 110, magneticparticles 191 are moved in a vertical direction within liquid container110. In this case, the direction in which magnetic particles 191 areattracted by the strong magnetic force is alternately reversed in thethickness direction of sample analysis cartridge 100. The permanentmagnets 520 on the both surfaces of sample analysis cartridge 100 aremoved to further facilitate the agitation of the coupled body of labeledsubstance 193 and magnetic particle 191.

(Configuration of Air Chamber)

FIG. 17 illustrates a configuration example of air chamber 130.

Air chamber 130 is connected to valve part 131 and a portion of an airsupply destination. Valve part 131 is connected to air chamber 130 andair flow path 132 connected to the outside of sample analysis cartridge100, respectively. The air outside the cartridge is taken into airchamber 130 from air flow path 132 through valve part 131.

Air chamber 130 and valve part 131 have a structure for activation byplunger 530. For example, air chamber 130 and valve part 131 are eachformed into a recessed shape in the surface of cartridge main body 100 aso as to have an opening in the upper part thereof, and covered withsheet 133 that is an elastic member.

Valve part 131 can close the connection portion with air flow path 132by plunger 530 entering the inside from the outside through sheet 133.Air chamber 130 is filled with air. Air chamber 130 can discharge theinternal air to the supply destination flow path by plunger 530 pushingsheet 133 into air chamber 130 from the outside. Sample analyzer 500discharges the air in air chamber 130 to the supply destination flowpath by using plunger 530 to close valve part 131 and push sheet 133into air chamber 130. Here, the operation of pushing sheet 133 into airchamber 130 by using plunger 530 is described as “activating air chamber130”. The operation of pushing sheet 133 into valve part 131 by usingplunger 530 is described as “closing valve part 131”.

In a state where valve part 131 is not closed, air chamber 130 comesinto contact with the air outside the cartridge through valve part 131and air flow path 132. When sample analysis cartridge 100 is heated byheat blocks 510, the air in air chamber 130 expands. When the air in airchamber 130 expands, an increase in internal pressure of air chamber 130causes the air to flow out to the flow path of air supply destination.As a result, the liquid in sample analysis cartridge 100 may beunintentionally operated. A change in internal pressure due to theexpansion of the air in air chamber 130 is suppressed by air chamber 130coming into contact with the air outside sample analysis cartridge 100through air flow path 132. Thus, unintentional operation of the liquidin sample analysis cartridge 100 can be suppressed.

Air chambers 130 and valve parts 131 may be provided according to thenumber of the air supply destinations. Sample analyzer 500 may includethe same number of plungers 530 as those of air chambers 130 and valveparts 131 or may include a smaller number of plunger 530 than those ofair chambers 130 and valve parts 131. In such a case, air chambers 130and valve parts 131 to be activated may be switched by moving plungers530. The sample analyzer can be reduced in size for the reduction in thenumber of plungers 530.

The arrangement positions of air chambers 130 and valve parts 131 may beset according to the configuration of sample analysis cartridge 100.When plunger 530 is moved, air chambers 130 or valve parts 131 may belinearly arranged. Accordingly, plunger 530 needs only be linearly movedin the arrangement direction. Thus, the movement mechanism can besimplified to reduce the size of the sample analyzer.

(Flow Path Structure)

Sample analysis cartridge 100 has a flow path structure that facilitatesmixing of liquids on a flow path.

<Sample Flow Path>

Next, a configuration of sample flow path 140 is described. Sampleanalysis cartridge 100 includes sample flow path 140 for transporting amixed liquid of a reagent and a sample containing test substance 190 toliquid reaction part 112. FIG. 18 is a schematic diagram of the sampleflow path. On sample flow path 140, air chamber 130 a agitates the mixedliquid of the sample and the reagent by the air pressure in sample flowpath 140, and transports the mixed liquid to liquid reaction part 112.Thus, since the mixed liquid of the sample and the reagent can beagitated in the sample flow path 140, the mixed liquid can be suppliedto liquid reaction part 112 in a state where test substance 190 and thereagent are sufficient reacted.

Sample flow path 140 includes, for example, R1 reagent tank 141, firstportion 142, second portion 143, and mixing part 144. R1 reagent tank141 has one end connected to air chamber 130 a through first portion142. R1 reagent tank 141 has the other end connected to blood cellseparator 120 through second portion 143. R1 reagent tank 141 isconnected to liquid reaction part 112 through mixing part 144. R1reagent tank 141 stores the R1 reagent. In this embodiment, sampleanalyzer 500 uses air chamber 130 a to alternately generate a positivepressure and a negative pressure, thereby moving back and forth a mixedliquid of the sample and the R1 reagent within sample flow path 140.Thus, the mixed liquid can be efficiently agitated within sample flowpath 140. The volume of sample flow path 140 is larger than that of themixed liquid. Therefore, the mixed liquid can be easily moved back andforth within sample flow path 140.

Mixing part 144 has one end connected to a joint portion between secondportion 143 and a flow path from blood cell separator 120. Mixing part144 has the other end connected to liquid reaction part 112. Mixing part144 includes straight part 144 a, bent part 144 b, and meander part 144c.

Straight part 144 a partially overlaps with meander part 144 c as seenfrom the short direction of sample analysis cartridge 100. Straight part144 a has narrow flow path part 144 d, for example. Narrow flow pathpart 144 d can stop the sample flowing through sample flow path 140 atnarrow flow path part 144 d. Mixing part 144 does not have to includestraight part 144 a.

Bent part 144 b connects straight part 144 a to meander part 144 c. Bentpart 144 b is formed into an approximately U-shape. In a schematic view,sample flow path 140 is bent approximately 180 degrees at bent part 144b. Thus, the movement distance of the mixed liquid can be increased, andthus the mixed liquid can be efficiently mixed. Mixing part 144 does nothave to include bent part 144 b.

In a planar view, a sine-wave shape or the like can be adopted as theshape of meander part 144 c. The agitation of the mixed liquid can befacilitated by meander part 144 c changing the circulation direction ofthe mixed liquid. Meander part 144 c includes dilated parts 144 e.Dilated parts 144 e are formed by increasing the cross-sectional area ofmeander part 144 c on the plane having a normal line in the flow pathdirection of the mixed liquid. Dilated parts 144 e accumulate the flowof the mixed liquid and capture air bubbles generated in the mixedliquid flowing through the flow path. Dilated parts 144 e can remove theair bubbles from the mixed liquid flowing through meander part 144 c.Moreover, dilated parts 144 e can complicate the flow of the mixedliquid with changes in cross-sectional area, thereby facilitating theagitation of the mixed liquid. Mixing part 144 does not have to includemeander part 144 c. Meander part 144 c may include only one dilated part144 e. Alternatively, meander part 144 c does not have to includedilated parts 144 e.

Mixing part 144 is connected to liquid reaction part 112 from the backsurface side of sample analysis cartridge 100, for example. Thus, themixed liquid of the sample and the R1 reagent can be discharged toliquid reaction part 112 from below.

<Mixed Liquid Flow Path>

FIG. 19 is a schematic diagram of mixed liquid flow path 150. Mixedliquid flow path 150 is formed in a region between passage part 116 anddetection tank 170, and connects passage part 116 to detection tank 170.Mixed liquid flow path 150 includes, for example, dispersion portion151, first portion 152, and second portion 153. Mixed liquid flow path150 has a structure to disperse complex 190 c containing magneticparticles 191 and labeled substance 192 into the buffer liquid that isthe R4 reagent. On mixed liquid flow path 150, air chamber 130 btransports the mixed liquid of the buffer liquid and magnetic particles191 carrying complex 190 c to detection tank 170. Thus, magneticparticles 191 transported in an aggregated state by magnetic force aredispersed in the buffer liquid and transported to detection tank 170while being dispersed in the buffer liquid. Accordingly, test substance190 can be easily detected in detection tank 170.

Mixed liquid flow path 150 joins passage part 116. Mixed liquid flowpath 150 agitates the mixed liquid of complex 190 c and the R4 reagentby moving the mixed liquid back and forth in mixed liquid flow path 150with the air pressure. In this embodiment, the mixed liquid is movedback and forth within mixed liquid flow path 150 by air chamber 130 balternately generating a positive pressure and a negative pressure.Thus, the mixed liquid can be efficiently agitated in the flow path. Thevolume of mixed liquid flow path 150 is larger than the volume of themixed liquid. Thus, the mixed liquid can be easily moved back and forthin the mixed liquid flow path 150.

FIG. 20 is a schematic cross-sectional view along mixed liquid flow path150. Dispersion portion 151 includes connection portion 151 a connectedto passage part 116 and first portion connection portion 151 b connectedto first portion 152. Dispersion portion 151 includes fourth liquidcontainer 115.

Fourth liquid container contains the R4 reagent. Fourth liquid container115 is connected to connection portion 151 a at one side portion 151 dextending in the thickness direction (Z direction) of cartridge mainbody 100 a. Fourth liquid container 115 is connected to first portionconnection portion 151 b at the other side portion 151 e extending inthe Z direction. At an upper end of one side portion 151 d, reduceddiameter part 151 f is formed. At an upper end of the other side portion151 e, reduced diameter part 151 g is formed.

Step 151 h protruding in a Z1 direction is formed on reduced diameterpart 151 f.

First portion 152 is disposed at a position lower than detection tank170 in the Z direction (thickness direction of sample analysis cartridge100). First portion 152 has one end connected to dispersion portion 151and the other end connected to second portion 153. First portion 152 isformed so as to extend along the surface of cartridge main body 100 a.Thus, the mixed liquid of complex 190 c and the R4 reagent can be movedwithin a wide range and efficiently agitated.

Second portion 153 is disposed at a position lower than detection tank170 in the Z direction (thickness direction of sample analysis cartridge100). Second portion 153 extends in the Z direction. Second portion 153has one end connected to first portion 152 and the other end connectedto detection tank 170. Thus, the mixed liquid of complex 190 c and theR4 reagent can be discharged to detection tank 170 from below.

Referring back to FIG. 19, first portion 152 of mixed liquid flow path150 may be formed into a meandering shape in a planar view, for example.Thus, mixed liquid flow path 150 can be easily elongated. As a result,the mixed liquid of complex 190 c and the R4 reagent can be efficientlyagitated within mixed liquid flow path 150. As the meandering shape offirst portion 152 in mixed liquid flow path 150, a sine-wave shape orthe like can be adopted. Thus, mixed liquid flow path 150 can be easilyformed into the meandering shape, and the mixed liquid of complex 190 cand the R4 reagent can be efficiently agitated within mixed liquid flowpath 150.

<Other Configuration Examples of Mixed Liquid Flow Path>

FIGS. 21 to 25 illustrate other configuration examples of mixed liquidflow path 150. As illustrated in FIG. 21, first portion 152 of mixedliquid flow path 150 may be formed such that the cross-sectionperpendicular to the extending direction of mixed liquid flow path 150differs in the extending direction of mixed liquid flow path 150. Thus,unlike the case where mixed liquid flow path 150 is formed into themeandering shape, mixed liquid flow path 150 can be formed in a compactsize, and the mixed liquid of complex 190 c and the R4 reagent can beefficiently agitated within mixed liquid flow path 150.

As illustrated in FIG. 22, mixed liquid flow path 150 may have apartially overlapping part by forming mixed liquid flow path 150 into athree-dimensionally intersecting shape.

As illustrated in FIG. 23, fourth liquid container 115 may be disposedin a flow path portion connecting air chamber 130 to mixed liquid flowpath 150.

As illustrated in FIG. 24, fourth liquid container 115 may be configuredto supply the R4 reagent to detection tank 170 by using a negativepressure from air chamber 130. In this case, fourth liquid container 115has one side (upstream side) connected to an air inlet. Air chamber 130is connected to detection tank 170, and the negative pressure generatedin air chamber 130 discharges the R4 reagent to first portion 152.

As illustrated in FIG. 25, both ends of fourth liquid container 115 maybe connected to passage part 116 and detection tank 170, and the mixedliquid may be discharged to detection tank 170 by the negative pressurefrom air chamber 130 connected to detection tank 170.

<R5 Flow Path>

FIG. 26 illustrates a configuration example of R5 flow path 160. R5 flowpath 160 includes, for example, R5 reagent tank 161, first portion 162,and second portion 163.

R5 reagent tank 161 has one end connected to air chamber 130 c throughfirst portion 162. R5 reagent tank 161 has the other end connected todetection tank 170 through second portion 163. R5 reagent tank 161stores the R5 reagent. The R5 reagent is discharged to detection tank170 by the air pressure in air chamber 130 c.

As the configuration of R5 reagent tank 161, basically the sameconfiguration as that of fourth liquid container 115 illustrated in FIG.20 can be adopted. More specifically, R5 reagent tank 161 includesreagent storage portion 161 a formed near the bottom of cartridge mainbody 100 a. One side of reagent storage portion 161 a is connected tofirst portion 162 through portion 161 b extending in the thicknessdirection (Z direction) of cartridge main body 100 a. The other side ofreagent storage portion 161 a is connected to second portion 163 throughportion 161 c extending in the Z direction. At an upper end of portion161 b, reduced diameter part 161 d is formed. At an upper end of portion161 c, reduced diameter part 161 e is formed.

Second portion 163 is connected to detection tank 170 from the backsurface side of cartridge 100, for example. Thus, the R5 reagent can bedischarged to detection tank 170 from below.

(Configuration of Detection Tank)

Detection tank 170 provides a measurement region for optical measurementof test substance 190 (complex 190 c reacted with the R5 reagent). Asillustrated in a configuration example of FIGS. 27 and 28, detectiontank 170 includes, for example, liquid disposition part 171, flowcontrol wall 172, step 173, external region 174, and air channel 175.

Liquid disposition part 171 is formed to be concave toward the back sidefrom the front side surface of cartridge main body 100 a. Liquiddisposition part 171 accumulates the mixed liquid discharged from mixedliquid flow path 150 and the R5 reagent discharged from the R5 flow path160. Detection tank 170 reacts labeled substance 193 in complex 190 ccontained in the mixed liquid with the substrate contained in the R5reagent.

Flow control wall 172 protrudes from liquid disposition part 171. Flowcontrol wall 172 is tilted toward the side where the exit of secondportion 153 and exit of second portion 163 are arranged from theperipheral portion of liquid disposition part 171. Moreover, flowcontrol wall 172 is linearly formed.

Step 173 is disposed along the periphery of liquid disposition part 171.Step 173 surrounds liquid disposition part 171. The mixed liquid addedwith the R5 reagent is accumulated in liquid disposition part 171 on theinside of step 173 in a planar view.

External region 174 is a region outside step 173. External region 174 isfirmed into an arc shape in the planar view.

Air channel 175 is formed on the outside of external region 174. Airchannel 175 is a groove formed in the front side surface of cartridgemain body 100 a. Air channel 175 is connected to liquid disposition part171 through two connection parts 175 a. Air channel 175 is connected toair flow path 132 through a hole 175 b. Connection parts 175 a aredisposed near second portion 153 of mixed liquid flow path 150 andsecond portion 163 of R5 flow path 160.

When detection tank 170 is thus configured, air bubbles can escapethrough air channel 175 even if the air bubbles are discharged intoliquid disposition part 171 after the liquid is discharged into liquiddisposition part 171 from mixed liquid flow path 150 and R5 flow path160.

[Configurations of Respective Parts in Sample Analyzer]

Configurations of the respective parts in sample analyzer 500 aredescribed. FIG. 29 illustrates a configuration example of sampleanalyzer 500. In the configuration example of FIG. 29, setting part 550is integrated with heat block 510. Setting part 550 and heat block 510may be separately provided.

Sample analysis cartridge 100 is held by heat block 510. In theconfiguration example of FIG. 29, magnet unit 501, plunger unit 502, anddetector 540 are arranged on the sides of heat block 510.

Magnet unit 501 includes: permanent magnet 520 as magnetic source 50;and movement mechanism 521 configured to move permanent magnet 520relative to sample analysis cartridge 100. Movement mechanism 521 canmove permanent magnet 520 in a horizontal direction and in a verticaldirection (cartridge thickness direction). When liquid containers 110,between which magnetic particles 191 are transported by the magneticforce, are linearly arranged, movement mechanism 521 may horizontallymove only in one straight axial direction along the arrangementdirection of respective liquid containers 110. Movement mechanism 521enables the agitation operation illustrated in FIG. 16 by movingpermanent magnet 520 in the vertical direction relative to liquidcontainers 110 in sample analysis cartridge 100 set in setting part 550.

When permanent magnets 520 are provided above and below sample analysiscartridge 100 set in setting part 550, two magnet units 501 aredisposed. In this case, the horizontally moving structure of movementmechanism 521 may be shared by two magnet units 501. In this case,movement mechanism 521 enables the agitation operation illustrated inFIG. 16B by moving the permanent magnet 520 provided above the cartridgeand permanent magnet 520 provided below the cartridge alternately closeto the liquid containers 110 in sample analysis cartridge 100 set insetting part 550.

Plunger unit 502 includes, for example: plunger 530 configured toactivate air chamber 130 and valve part 131; and movement mechanism 531configured to move plunger 530 relative to sample analysis cartridge100. Movement mechanism 531 can move plunger 530 in the verticaldirection. When air chamber 130 and valve part 131 are linearlyarranged, movement mechanism 531 may horizontally move only in onestraight axial direction along the arrangement direction of air chamber130 and valve part 131. When the same number of plungers 530 as those ofair chambers 130 and valve parts 131 are provided, the horizontalpositions of plungers 530 can be fixed. Thus, movement mechanism 531 maymove only in the vertical direction.

Detector 540 is disposed at a position close to detection tank 170 insample analysis cartridge 100. In FIG. 29, detector 540 is disposed at aposition immediately below detection tank 170.

(Plunger)

In this embodiment, the liquid is transported by activating air chamber130 in a closed state of valve part 131. Thus, plunger 530 for airchamber 130 and plunger 530 for valve part 131 may be configured so asto individually move up and down. As in a configuration exampleillustrated in FIG. 30, plungers 530 may be configured so as to move upand down all together. In such a case, the sample analyzer can bereduced in size by simplifying the mechanism for moving plungers 530 inthe vertical direction.

FIG. 30 illustrates the configuration example for activating air chamber130 and valve part 131 all together. Plunger 530 a is a plunger foractivating air chamber 130, and plunger 530 b is a plunger for openingand closing valve part 131. Respective plungers 530 a and 530 b areattached to holding block 532, and moved up and down all together bymovement of holding block 532.

Plunger 530 a is fixed to holding block 532. Plunger 530 b is attachedto holding block 532 in a state of being movable up and down relative toholding block 532. Plunger 530 b is provided with energizing member 533configured to energize plunger 530 b in a downward direction protrudingfrom holding block 532.

Thus, when holding block 532 is lowered toward sample analysis cartridge100, plunger 530 b first closes valve part 131. When holding block 532is further lowered in this state, energizing member 533 is compressedand plunger 530 b is moved relative to holding block 532. Thus, theposition of plunger 530 b can be maintained even if holding block 532 ismoved. Therefore, by moving holding block 532 up and down in the closedstate of valve part 131, plunger 530 a can move the liquid back andforth within the flow path by moving up and down relative to air chamber130. Moreover, by further lowering holding block 532, the liquid can besent to the portion of supply destination from the flow path.

(Temperature Control in Cartridge)

In this embodiment, sample analyzer 500 controls the temperatures of thesample and reagent in sample analysis cartridge 100 to those required inthe assay. Sample analyzer 500 uses heat block 510 to control thetemperatures of the sample and reagent in sample analysis cartridge 100.Heat block 510 performs the temperature control using a heating wire orthe like which generates heat with not-illustrated power supply, forexample. When not only heating but also cooling is required, athermoelectric element such as a Peltier element, for example, is usedas heat block 510.

FIG. 31 illustrates a configuration example of the heat blocks accordingto this embodiment.

Heat blocks 510 are disposed on the upper and lower surfaces of sampleanalysis cartridge 100, for example. Heat block 510 may be disposed onany one of the upper and lower surfaces of sample analysis cartridge100. In this embodiment, the upper surface of sample analysis cartridge100 is a surface corresponding to the direction in which permanentmagnet 520 for transporting magnetic particles 191 is disposed.

Heat block 510 disposed on the lower surface of sample analysiscartridge 100 is configured to cover at least a part of or all of afluid structure associated with reaction. The fluid structure associatedwith reaction is the portion corresponding to sample flow path 140,liquid reaction part 112, second liquid container 114, mixed liquid flowpath 150, R5 flow path 160, and the like, for example. Heat block 510disposed on the lower surface may be configured to cover a fluidstructure associated with the transportation of magnetic particles 191.The fluid structure associated with the transportation of magneticparticles 191 is the portion corresponding to first liquid container111, liquid reaction part 112, third liquid container 113, second liquidcontainer 114, fourth liquid container 115, passage part 116 providedbetween liquid containers 110 (see FIG. 4) in this embodiment. Heatblock 510 disposed on the lower surface of sample analysis cartridge 100may be configured to cover approximately the entire lower surface ofsample analysis cartridge 100. The temperature control efficiency ofsample analysis cartridge 100 is improved by heat block 510 coveringapproximately the entire lower surface of sample analysis cartridge 100.

Heat block 510 disposed on the upper surface of sample analysiscartridge 100 has holes 511 for plunger 530 and permanent magnet 520 toaccess sample analysis cartridge 100. Hole 511 for plunger 530 to accesssample analysis cartridge 100 is provided at the position correspondingto air chamber 130 in sample analysis cartridge 100. Hole 511 forpermanent magnet 520 to access sample analysis cartridge 100 is extendedin the longitudinal direction of sample analysis cartridge 100. The holeextended in the longitudinal direction of sample analysis cartridge 100enables permanent magnet 520 to be moved in the transportation directionof magnetic particles 191 while staying close to sample analysiscartridge 100.

As indicated by the broken lines in FIG. 31, a reduced thickness portionmay be provided in heat block 510 on the lower surface of sampleanalysis cartridge 100. In FIG. 31, heat block 510 on the lower surfaceof sample analysis cartridge 100 has groove 512 extending in thelongitudinal direction of sample analysis cartridge 100.

Sample analyzer 500 applies magnetic force to sample analysis cartridge100 by inserting permanent magnet 520 provided on the lower surface ofsample analysis cartridge 100 into groove 512. Groove 512 in heat block510 does not penetrate heat block 510 from the lower surface to theupper surface. Thus, the magnetic force can be applied from the lowersurface of sample analysis cartridge 100 without impairing the functionto control the temperature on approximately the entire lower surface ofsample analysis cartridge 100.

In Patent Document 1, the microchannels connecting the liquid containerscontaining the liquid are filled with the liquid. Thus, the movement ofthe magnetic particles makes it likely for the liquid in the liquidcontainer to be mixed into the liquid in the liquid container adjacentthereto. As a result, analysis precision for the test substance may bereduced.

The embodiments described above suppresses the mixing of a liquid in aliquid container into a liquid in a liquid container adjacent thereto bymovement of magnetic particles in sample measurement using a sampleanalysis cartridge.

Note that the embodiment disclosed herein is merely illustrative in allaspects and should not be recognized as being restrictive. The scope ofthe invention is defined by the scope of the claims rather than by theabove description of the embodiment, and is intended to include themeaning equivalent to the scope of the claims and all modificationswithin the scope.

The invention claimed is:
 1. A method of detecting a test substancecontained in a sample, comprising: applying a sample to a cartridgecomprising: at least first and second chambers filled with liquid-basedfirst and second reagents, respectively; and a passage adjacent to anupper surface of the cartridge and connecting the first and secondchambers with a gas-phase space, wherein openings are formed in upperparts of the first and second chambers, the first and second chambersare connected through the respective openings by the passage, thepassage is provided above the first and second chambers and covered witha cover part, and the first and second chambers are filled with thefirst and second reagents up to the cover part so that a first liquidphase formed by the first reagent and a second liquid phase formed bythe second reagent are separated with the gas-phase space in thepassage; transferring at least a part of the sample to the first chamberso that magnetic particles contained in the first reagent react with atest substance in the sample, the magnetic particles carrying the testsubstance in response to the magnetic particles reacting with the testsubstance; attracting, in the first liquid phase of the first reagent,the magnetic particles close to the cover part with a magnetic source;transferring, by moving the magnetic source along the cover part, acomplex of the test substance and the magnetic particles from the firstliquid phase to the second liquid phase through the gas-phase space sothat the complex reacts with a labeled substance contained in the secondreagent; and detecting the test substance in the complex based on thelabeled substance.
 2. The method of detecting a test substance,according to claim 1, wherein the magnetic particles are moved in avertical direction within the first chamber by moving the magneticsource.
 3. The method of detecting a test substance, according to claim1, wherein the cartridge further includes a liquid reaction part inwhich a reaction of the magnetic particles with the test substance takesplace, and the magnetic particles are transported from the first chamberto the liquid reaction part through the gas-phase space of the passage.4. The method of detecting a test substance, according to claim 3,wherein the cartridge further comprises a sample flow path connected tothe liquid reaction part, and a mixture of the first reagent and thesample containing the test substance is agitated by an air pressureinside the sample flow path, and the mixture is discharged to the liquidreaction part.
 5. The method of detecting a test substance, according toclaim 1, wherein the cartridge further comprises a third chamber that islocated between the first and second chambers and contains a cleaningliquid, and unwanted substances attached to the magnetic particles aredispersed into the cleaning liquid by transporting the magneticparticles coupled to the test substance to the third chamber through thegas-phase space of the passage.
 6. The method of detecting a testsubstance, according to claim 1, wherein the cartridge further comprisesa third chamber containing a cleaning liquid, and the complex of thetest substance and the labeled substance is carried by the magneticparticles by transporting the magnetic particles coupled to the testsubstance from the third chamber to the second chamber adjacent theretothrough the gas-phase space of the passage.
 7. The method of detecting atest substance, according to claim 6, wherein the magnetic particles aresequentially transported to the third chamber on an upstream side, thesecond chamber, and the third chamber on a downstream side in therecited order through the gas-phase space of the passage.
 8. The methodof detecting a test substance, according to claim 1, wherein thecartridge further comprises a fourth chamber that contains a bufferliquid, and the magnetic particles carrying the complex of the testsubstance and the labeled substance are dispersed into the buffer liquidby transporting the magnetic particles carrying the complex to thefourth chamber through the gas-phase space of the passage.
 9. The methodof detecting a test substance, according to claim 8, wherein thecartridge further includes a detection tank in which a reaction of thelabeled substance with a substrate takes place, and a mixed liquid ofthe complex and the buffer liquid in the fourth chamber is transportedto the detection tank through a mixed liquid flow path.
 10. The methodof detecting a test substance, according to claim 1, wherein an area ofa bottom inner surface of each of the first and second chambers islarger than an opening area of the openings that connect each of thefirst and second chambers to the passage.
 11. A method of detecting atest substance contained in a sample by use of a cartridge, comprising:receiving a sample with the cartridge; transferring at least a part ofthe sample to a first chamber, of the cartridge, which accommodates aliquid-based first reagent filled up to a cover part, so that magneticparticles contained in the first reagent react with a test substance inthe sample, the magnetic particles carrying the test substance inresponse to the magnetic particles reacting with the test substance;attracting, in a first liquid phase formed by the first reagent, themagnetic particles close to the cover part with a magnetic source;transferring, by moving the magnetic source along the cover part, acomplex of the test substance and the magnetic particles from the firstliquid phase to a second liquid phase formed by a second liquid-basedreagent through a gas phase defined by a passage connecting the firstchamber and a second chamber, of the cartridge, which accommodates thesecond reagent filled up to the cover part, so that the complex reactswith a labeled substance contained in the second reagent, wherein thepassage is provided adjacent to an upper surface of the cartridge andwherein openings are formed in upper parts of the first and secondchambers, and the first and second chambers are connected through therespective openings by the passage, and wherein the passage is providedabove the first and second chambers and covered with the cover part sothat the first reagent and the second reagent filled up to the coverpart are separated with the gas-phase in the passage; and detecting thetest substance in the complex based on the labeled substance.